In addition to the molecular mechanisms tumors employ to resist chemotherapy or immunotherapy, a number of physiologic variables that influence cancer treatment have recently been identified. One of these variables, namely interstitial pressure (IP), influences convection and diffusion, which are the main means of transport for nutrients and therapeutic agents through the interstitial space of tumors and normal tissues. Animal and computer models suggest that elevated IP can slow antibody movement through tumors to such an extent that it could take up to 7 months for an IgG molecule to travel 1 cm through the tumor interstitium. This study seeks to define IP in a variety of human malignancies and its relationship to response. The impact of biologic and chemotherapy treatment on IP is also being studied. Thus far, 39 patients have had IP measured by the wick-in-needle technique in peripheral lymph nodes and subcutaneous nodules. The IP in melanoma unresponsive to treatment is approximately 10-fold higher than chemotherapy sensitive lymphomas. Biologic agents delivered systemically or intratumorally increase IP in solid tumors by 5 fold. AIkylating agents cause transient IP increases in lymphoma. Biologic agents delivered subcutaneously at sites distant from the tumor also result in transient IP elevations in normal tissues. Palpation of tumors or normal tissues up to 15 cm away from the tumor can alter intratumoral IP acutely. The IP in unresponsive melanoma patients is significantly greater than in chemotherapy responsive lymphomas. Lymphomas that recur and become unresponsive develop elevated IP. The procedure has been well tolerated thus far. One patient had dramatic growth in a measured tumor nodule; however his other visceral disease also progressed. There have been no interruptions in patient treatment protocols from IP measurements.